Temporomandibular joint disorders represent a major health problem and persistent TMJD pain is difficult to manage successfully. The majority of cases involve muscle. Laboratory evaluations proposed in this application permit new and critically important insight into the pathogenesis of persistent TMJD pain. We propose the use of approaches from several different scientific disciplines, such as genetics, endocrinology, neurobiology of pain and imaging of peripheral tissue to probe and understand the system response of human subjects with respect to disease characteristics of TMJD and for which measurement opportunities in animals are limited. Based on supporting data, this research aims to provide new knowledge regarding the significance of a candidate gene that appears to exert a strong effect on critical hallmark features of persistent TMJD muscle pain. Because sensitivity to pain and inhibition of pain are traits of considerable variability, we will study the effect of this gene on subject's response characteristics to experimentally induced jaw muscle pain. Furthermore, because women in their reproductive age make up the majority of patients treated with TMJD, our proposed research also focuses on whether estrogen significantly alters the system's response in subjects of a particular genotype.